The purpose of this project is to identify the determinants of non- insulin-dependent diabetes, various types of arthritis, and gallbladder disease, and elucidate the natural history of the diseases and their complications. Genetic and environmental risk factors for non-insulin-dependent diabetes and vascular complications of diabetes have been studied in the Pima Indians. The residents of the study area, currently numbering approximately 5000 people, have participated in a longitudinal population study for the last 22 years, allowing observations of the natural history of diabetes mellitus and its complications. Risk factors for obesity, hypertension, and cholelithiasis are also studied, along with the relationships of these diseases to diabetes. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose tolerance, and diabetes in relatives are assessed. Assessments of occupational and leisure-time physical activity and diet will be added. Risk factors for the major complications of diabetes, retinopathy, nephropathy, coronary artery disease, and peripheral vascular disease are determined by longitudinal followup of diabetic subjects. Methods for ascertainment of these complications include fundus photography, measurement of urine albumin and serum creatinine concentrations, electrocardiography, and documentation of lower extremity amputations secondary to gangrene. The severity of abnormality of glucose homeostasis is assessed be measurement of plasma glucose and serum insulin concentrations during glucose tolerance tests and measurement of glycosylated hemoglobin. The effects of these diseases and their complications on mortality are assessed by analysis of death certificates and examination of medical records for the classification of causes of death. This study has shown diabetes to be a serious and common disease with both genetic and environmental components. The complications, especially when involving the kidney, are an important cause of increased mortality.